Extracellular vesicles derived from macrophages display glycyl‐tRNA synthetase 1 and exhibit anti‐cancer activity

Goughnour, Peter C.; Park, Min-Chul; Kim, Sang Bum; Jun, Sangmi; Yang, Won-Mo; Chae, Sehyun; Cho, Seong-Min; Song, Chihong; Lee, Ji‐Hyun; Hyun, Jaekyung; Kim, Byung Gyu; Hwang, Daehee; Jung, Hyun Suk; Gho, Yong Song; Kim, Sung Hoon

doi:10.1002/jev2.12029

Cited by 16 publications

(12 citation statements)

References 63 publications

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“…While not discussed in this review, it is important to note that macrophages also secrete EVs within the TME that are able to drive or inhibit tumor progression (Goughnour et al, 2020;Zhang et al, 2020;Chang et al, 2021;Liu et al, 2021;Xavier et al, 2021). This cross-talk between tumors and macrophages, can result in complex paracrine and autocrine circuits that affect disease progression.…”

Section: Discussionmentioning

confidence: 99%

Tumor-Derived Extracellular Vesicles: A Means of Co-opting Macrophage Polarization in the Tumor Microenvironment

Reed

Schorey

D’Souza‐Schorey

2021

Front. Cell Dev. Biol.

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Extracellular vesicles (EVs) are a heterogeneous population of membrane-bound parcels of bioactive proteins, nucleic acids, and lipids released from almost all cell types. The diversity of cargo packaged into EVs proffer the induction of an array of effects on recipient cells. EVs released from tumor cells have emerged as a vital means of communication and immune modulation within the tumor microenvironment (TME). Macrophages are an important contributor to the TME with seemingly paradoxical roles promoting either pro- or anti-tumoral immune function depending on their activated phenotypes. Here, we discuss the influence of tumor-derived extracellular vesicles on the functional plasticity of macrophages in tumor progression.

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Section: Discussionmentioning

confidence: 99%

Tumor-Derived Extracellular Vesicles: A Means of Co-opting Macrophage Polarization in the Tumor Microenvironment

Reed

Schorey

D’Souza‐Schorey

2021

Front. Cell Dev. Biol.

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“…Moreover, CPT1A plays a crucial role in radioresistant and chemoresistant phenotypes in diverse cancer types [ 41 , 42 , 82 ]. Equally, altered protein levels of FLNA, HSPA7, HGF, ERO1A, and GARS1, have been related to cancer migration, adhesion, poor patient prognosis, and metastasis [ 48 , 49 , 50 , 83 , 84 ]. Particularly, filamin A (FLNA), a cytoskeleton regulator, has been reported as taking on opposite roles depending on the cancer type [ 47 ].…”

Section: Discussionmentioning

confidence: 99%

Reduced RBPMS Levels Promote Cell Proliferation and Decrease Cisplatin Sensitivity in Ovarian Cancer Cells

Rabelo-Fernández

Santiago-Sánchez

Sharma

et al. 2022

IJMS

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Worldwide, the number of cancer-related deaths continues to increase due to the ability of cancer cells to become chemotherapy-resistant and metastasize. For women with ovarian cancer, a staggering 70% will become resistant to the front-line therapy, cisplatin. Although many mechanisms of cisplatin resistance have been proposed, the key mechanisms of such resistance remain elusive. The RNA binding protein with multiple splicing (RBPMS) binds to nascent RNA transcripts and regulates splicing, transport, localization, and stability. Evidence indicates that RBPMS also binds to protein members of the AP-1 transcription factor complex repressing its activity. Until now, little has been known about the biological function of RBPMS in ovarian cancer. Accordingly, we interrogated available Internet databases and found that ovarian cancer patients with high RBPMS levels live longer compared to patients with low RBPMS levels. Similarly, immunohistochemical (IHC) analysis in a tissue array of ovarian cancer patient samples showed that serous ovarian cancer tissues showed weaker RBPMS staining when compared with normal ovarian tissues. We generated clustered regularly interspaced short palindromic repeats (CRISPR)-mediated RBPMS knockout vectors that were stably transfected in the high-grade serous ovarian cancer cell line, OVCAR3. The knockout of RBPMS in these cells was confirmed via bioinformatics analysis, real-time PCR, and Western blot analysis. We found that the RBPMS knockout clones grew faster and had increased invasiveness than the control CRISPR clones. RBPMS knockout also reduced the sensitivity of the OVCAR3 cells to cisplatin treatment. Moreover, β-galactosidase (β-Gal) measurements showed that RBPMS knockdown induced senescence in ovarian cancer cells. We performed RNAseq in the RBPMS knockout clones and identified several downstream-RBPMS transcripts, including non-coding RNAs (ncRNAs) and protein-coding genes associated with alteration of the tumor microenvironment as well as those with oncogenic or tumor suppressor capabilities. Moreover, proteomic studies confirmed that RBPMS regulates the expression of proteins involved in cell detoxification, RNA processing, and cytoskeleton network and cell integrity. Interrogation of the Kaplan–Meier (KM) plotter database identified multiple downstream-RBPMS effectors that could be used as prognostic and response-to-therapy biomarkers in ovarian cancer. These studies suggest that RBPMS acts as a tumor suppressor gene and that lower levels of RBPMS promote the cisplatin resistance of ovarian cancer cells.

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“…For instance, macrophages are exposed to environmental stresses, such as nutrient deprivation, hypoxia, and the signaling factors, including HSPs, released from cancer cells. These macrophages could recruit diverse intracellular factors and package them into secretory vesicles to mediate the primary response against cancer cells until the immune surveillance system was activated [46]. It was also found that macrophages cultured in glucose-depleted medium secreted human glycyl-tRNA synthetase 1 (GARS1)-EVs, which involved an immunological defense response against tumorigenesis and could promote cancer cell death [46,47].…”

Section: Discussionmentioning

confidence: 99%

Exosome-Based Molecular Transfer Activity of Macrophage-Like Cells Involves Viability of Oral Carcinoma Cells: Size Exclusion Chromatography and Concentration Filter Method

Eguchi

Sogawa

et al. 2021

Cells

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Extracellular vesicles (EV) heterogeneity is a crucial issue in biology and medicine. In addition, tumor-associated macrophages are key components in cancer microenvironment and immunology. We developed a combination method of size exclusion chromatography and concentration filters (SEC-CF) and aimed to characterize different EV types by their size, cargo types, and functions. A human monocytic leukemia cell line THP-1 was differentiated to CD14-positive macrophage-like cells by stimulation with PMA (phorbol 12-myristate 13-acetate) but not M1 or M2 types. Using the SEC-CF method, the following five EV types were fractionated from the culture supernatant of macrophage-like cells: (i) rare large EVs (500–3000 nm) reminiscent of apoptosomes, (ii) EVs (100–500 nm) reminiscent of microvesicles (or microparticles), (iii) EVs (80–300 nm) containing CD9-positive large exosomes (EXO-L), (iv) EVs (20–200 nm) containing unidentified vesicles/particles, and (v) EVs (10–70 nm) containing CD63/HSP90-positive small exosomes (EXO-S) and particles. For a molecular transfer assay, we developed a THP-1-based stable cell line producinga GFP-fused palmitoylation signal (palmGFP) associated with the membrane. The THP1/palmGFP cells were differentiated into macrophages producing palmGFP-contained EVs. The macrophage/palmGFP-secreted EXO-S and EXO-L efficiently transferred the palmGFP to receiver human oral carcinoma cells (HSC-3/palmTomato), as compared to other EV types. In addition, the macrophage-secreted EXO-S and EXO-L significantly reduced the cell viability (ATP content) in oral carcinoma cells. Taken together, the SEC-CF method is useful for the purification of large and small exosomes with higher molecular transfer activities, enabling efficient molecular delivery to target cells.

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Extracellular vesicles derived from macrophages display glycyl‐tRNA synthetase 1 and exhibit anti‐cancer activity

Cited by 16 publications

References 63 publications

Tumor-Derived Extracellular Vesicles: A Means of Co-opting Macrophage Polarization in the Tumor Microenvironment

Tumor-Derived Extracellular Vesicles: A Means of Co-opting Macrophage Polarization in the Tumor Microenvironment

Reduced RBPMS Levels Promote Cell Proliferation and Decrease Cisplatin Sensitivity in Ovarian Cancer Cells

Exosome-Based Molecular Transfer Activity of Macrophage-Like Cells Involves Viability of Oral Carcinoma Cells: Size Exclusion Chromatography and Concentration Filter Method

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